6-arylamino pyridone carboxamide as MEK inhibitors

Abstract

The invention provides novel substituted 6-arylamino pyridone carboxamides represented by Formula I, or a pharmaceutically acceptable salt, solvate, poly-morph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. The invention further provides a method of treatment for inflammatory diseases, cancer and other hyperproliferative diseases in mammals, especially humans.

What is claimed is: 
     
       1. A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
            represents X—Y═W or W—Y═X, 
         X independently represent N, O, or S; 
         W is CR 2 , N, or S; 
         Y is N or CR 1 ; and 
         R 1  is selected from the group consisting of H and C 1 -C 6  alkyl; wherein each alkyl is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, amino, C 1 -C 6  alkylamino, diC 1 -C 6  alkylamino, and C 1 -C 6  heterocyclyl; 
         R 2  is selected from the group consisting of H and C 1 -C 10  alkyl, where each alkyl is unsubstituted or substituted with 1-3 substituents selected independently from halogen, hydroxyl, and C 1 -C 4  alkyl; 
         R 3  is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloalkylalkyl, where each alkyl, alkoxy, and cycloalkyl is unsubstituted or substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxyl, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy; 
         R 3′  is selected from the group consisting of H and C 1 -C 6  alkyl; 
         R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, SR 9 , and OR 9 ; 
         R 9  is selected from the group consisting of hydrogen and C 1 -C 10  alkyl; 
         R 13  is selected from the groups consisting of H and C 1 -C 6  alkyl; and 
         R 14  is selected from the groups consisting of H and C 1 -C 6  alkyl; 
         or a pharmaceutically acceptable salt, solvate, poly-morph, or tautomer thereof. 
       
     
     
       2. The compound according to  claim 1 , wherein Y is CR 1 . 
     
     
       3. The compound according to  claim 1 , wherein   represents X—Y═W; X is O or S; Y is CR 1 ; and W is CR 2 . 
     
     
       4. The compound according to  claim 1 , wherein R 3  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl and C 1 -C 4  alkoxy; C 1 -C 6  alkoxyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl; C 3 -C 6  cycloalkyl optionally substituted with C 1 -C 4  alkyl. 
     
     
       5. The compound according to  claim 4 , wherein R 3  is selected from the group consisting of C 1 -C 6  alkyl and C 1 -C 6  alkoxy, where alkyl and alkoxy are independently unsubstituted or substituted with one or more substituents selected independently from the group consisting of halogen and hydroxyl. 
     
     
       6. The compound according to  claim 1 , wherein R 4 , R 5 , R 6 , R 7  and R 8  are independently selected from H or halogen. 
     
     
       7. The compound according to  claim 6 , wherein one of R 4  and R 8  is fluorine or chlorine, and R 6  is iodine. 
     
     
       8. The compound according to  claim 7  which is selected from the following 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       10. A method for the treatment of a MEK mediated disorder or disease in a subject comprising administration of the compound of  claim 1 , wherein the MEK mediated disorder or disease is melanoma.